Cross-species malaria immunity induced by chemically attenuated parasites

Abstract

Vaccine development for the blood stages of malaria has focused on the induction of antibodies to parasite surface antigens, most of which are highly polymorphic. An alternate strategy has evolved from observations that low-density infections can induce antibody-independent immunity to different strains. To test this strategy, we treated parasitized red blood cells from the rodent parasite Plasmodium chabaudi with secocyclopropyl pyrrolo indole analogs. These drugs irreversibly alkylate parasite DNA, blocking their ability to replicate. After administration in mice, DNA from the vaccine could be detected in the blood for over 110 days and a single vaccination induced profound immunity to different malaria parasite species. Immunity was mediated by CD4 + T cells and was dependent on the red blood cell membrane remaining intact. The human parasite, Plasmodium falciparum, could also be attenuated by treatment with seco-cyclopropyl pyrrolo indole analogs. These data demonstrate that vaccination with chemically attenuated parasites induces protective immunity and provide a compelling rationale for testing a blood-stage parasite-based vaccine targeting human Plasmodium species.

Chemical Attenuation in the Development of a Whole-Organism Malaria Vaccine

“…The studies presented in this review provide evidence that immunization with malaria parasites, whether attenuated in vivo or in vitro, can induce protective parasite-specific immune responses. The protection provided can be both long lasting (30,43) and strain and species transcending (20,31,42,43). Chemically attenuated blood-stage vaccines may currently be difficult to implement in settings of malaria endemicity; however, novel strategies for cryopreservation and drug delivery are likely to reduce the barriers to these approaches in the near future.…”

“…In vitro chemical attenuation of blood-stage parasites has also been investigated using CM and TF-A (42,43). Immunization with either a single dose of P. chabaudi or three doses of P. yoelii chemically attenuated blood-stage parasites resulted in activation of both CD4 ϩ and CD8 ϩ T cells, and strong proliferative responses were induced against both homologous and heterologous parasites (42,43).…”

“…Immunization with either a single dose of P. chabaudi or three doses of P. yoelii chemically attenuated blood-stage parasites resulted in activation of both CD4 ϩ and CD8 ϩ T cells, and strong proliferative responses were induced against both homologous and heterologous parasites (42,43). Inoculation of chemically attenuated blood-stage P. yoelii parasites also induced parasite-specific antibodies (43).…”

“…Inoculation of chemically attenuated blood-stage P. yoelii parasites also induced parasite-specific antibodies (43). Mice were protected against homologous blood-stage parasite challenge, with protection being mediated by CD4 ϩ T cells (42,43) and B cells (in the case of the P. yoelii vaccine) (43). Immunization with chemically attenuated blood-stage parasites can also provide protection against challenge with heterologous blood-stage parasite strains (42,43) and species (42).…”

Vaccines to Accelerate Malaria Elimination and Eventual Eradication

“…Protection against challenge in a rodent study model was only apparent after several cycles of replication in the bloodstream and indicates that lack of protection against bloodstage challenge in human volunteers may have resulted from the necessarily early treatment with chloroquine (CQ), before the onset of symptoms. Attenuation by other means, either chemical (Good et al 2013) or genetic (Aly et al 2011), could potentially provide protection against homologous and heterologous blood-stage challenge. Complete sterilizing immunity against sporozoite challenge in a late-arresting GAP liver infection model is conferred by only two, rather than three, immunizations in other GAP/RAS models, suggesting that late schizont/merozoite antigen expression may be important.…”